Multifaceted Interventions to Amplify HSC Engraftment

多方面干预措施以扩大 HSC 植入

• 批准号: 7215215
• 负责人: CHRISTIE M Orschell
• 金额: $ 35.91万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7215215
• 关键词: Address; Adult; Bone Marrow; Bone Marrow Cells; Cell Transplants; Cell physiology; Cells; Cellular biology; Characteristics; Complex; Condition; Data; Disease; Dose; Engraftment; Gene-Modified; Goals; Hand; Hematopoiesis; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Home environment; Homing; Individual; Integration Host Factors; Intervention; Laboratories; Lead; Methods; Modality; Modeling; Mus; Non-Malignant; Numbers; One-Step dentin bonding system; Patients; Pattern; Physiological; Population; Probability; Process; Processed Genes; Protocols documentation; Publishing; Purpose; Radiation; Relative (related person); Research Personnel; Resolution; Scheme; Signal Transduction; Source; Stem cell transplant; Stem cells; Stromal Cells; Techniques; Testing; Therapeutic; Time; Toxic effect; Transplantation; Treatment Protocols; Umbilical Cord Blood; Work; base; chemotherapy; clinically relevant; conditioning; expectation; experience; gene correction; gene therapy; improved; in vivo; irradiation; older patient; programs; protocol development; reconstitution; response; self-renewal; size; success

DESCRIPTION (provided by applicant): The degree of donor cell engraftment following hematopoietic stem cell (HSC) transplantation is determined by the level of host stem cell competition. This competition is negligible after HSC-toxic effects of myeloablative conditioning, whereas the large number of host HSC remaining after non-myeloablative conditioning limits the success of non-ablative HSC transplantation (SCT). Increasing the number of transplanted HSC reportedly counteracts large reserves of host HSC, but excess donor HSC are not universally available for many patients or in certain types of SCT. The hypothesis of this proposal is that the overall engraftment potential of limited numbers of HSC can be increased by interventions at several different fronts in the SCT process, including modulation of the graft, conditioning regimens of the host, and exploitation of intrinsic host parameters. These interventions are aimed to increase hematopoietic potential, homing, survival and proliferation of transplanted HSC. The following three specific aims will be pursued: 1. Investigate how the graft itself can be manipulated prior to transplantation to increase its engraftment potential. 2. Examine how different host conditioning regimens impact homing, survival, proliferation, and subsequent engraftment potential of transplanted hematopoietic stem cells. 3. Identify and exploit intrinsic host parameters to increase overall engraftment potential of transplanted hematopoietic stem cells. A multi-factorial scheme utilizing sophisticated techniques and in vivo function to identify HSC will be employed to investigate these interventions using a murine SCT model. Our long-term goal is to understand the complex mechanisms by which transplanted HSC home to, survive within, and commence proliferation and self-renewal processes in host BM, and to manipulate these processes to increase engraftment potential of limited numbers of donor HSC. The significance of this work is the likelihood that it will provide new protocols in SCT for the ultimate benefit of patients receiving ex vivo manipulated grafts such as those processed for gene therapy purposes, or patients ineligible for myeloablative conditioning regimens or other protocols where the low ratio of donor to host HSC will likely lead to low or failed engraftment.

描述（由申请人提供）：造血干细胞（HSC）移植后供体细胞植入的程度取决于宿主干细胞竞争的水平。在清髓性预处理的HSC毒性作用后，这种竞争可以忽略不计，而在非清髓性预处理后剩余的大量宿主HSC限制了非清髓性HSC移植（SCT）的成功。据报道，增加移植HSC的数量抵消了宿主HSC的大量储备，但对于许多患者或某些类型的SCT，过量的供体HSC并不普遍可用。该建议的假设是，有限数量的HSC的总体植入潜力可以通过在SCT过程中的几个不同方面的干预来增加，包括移植物的调节、宿主的调节方案和内在宿主参数的利用。这些干预措施旨在增加移植HSC的造血潜能、归巢、存活和增殖。将努力实现以下三个具体目标： 1.研究移植物本身在移植前如何操作以增加其植入潜力。 2.研究不同的宿主预处理方案如何影响移植造血干细胞的归巢、存活、增殖和随后的植入潜力。 3.识别和利用内在宿主参数以增加移植造血干细胞的总体植入潜力。 一个多因素的计划，利用先进的技术和在体内的功能，以确定HSC将调查这些干预措施，使用小鼠SCT模型。我们的长期目标是了解移植的HSC在宿主骨髓中回家、存活并开始增殖和自我更新过程的复杂机制，并操纵这些过程以增加有限数量的供体HSC的植入潜力。这项工作的意义在于，它可能会提供新的SCT方案，以最终造福于接受离体操作移植物的患者，例如为基因治疗目的处理的移植物，或不适合清髓性预处理方案或其他方案的患者，其中供体与宿主HSC的低比例可能导致低或失败的植入。